title: [No relationship between tacrine cytotoxicity and its metabolisation by cytochrome P4501A2].
abstract: It has been suggested that tacrine (THA) induced hepatotoxicity was related to its metabolic pathway involving cytochrome P4501A2 (CYP1A2). Using a model of genetically modified cells we have demonstrated that THA induced a marked decrease in cell viability and a strong inhibition of RNA and protein synthesis. However, these cytotoxic effects did not differ in parental Chinese hamster V79 cells and variant cells expressing human or rat CYP1A2 as well in human HepG2 and Chang Liver cells despite their notable metabolism ability to metabolize THA to hydroxylated metabolites. These results strongly suggest that THA-induced cytotoxicity is not mediated by CYP1A2 indicating that THA could be toxic by direct inhibition at the ribosomial level.
authors.affiliation: Laboratoire de Toxicologie, Service de Pharmacie, CHU H.-Mondor, Créteil.
authors.forename: C
authors.initials: C
authors.lastname: Naud
authors.forename: G
authors.initials: G
authors.lastname: Benoit
authors.forename: M
authors.initials: M
authors.lastname: Simard
authors.forename: A
authors.initials: A
authors.lastname: Astier
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D019388:Cytochrome P-450 CYP1A2 / Q000494:pharmacology*; D006168:Guinea Pigs; D006801:Humans; D008099:Liver / Q000166:cytology / Q000473:pathology; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D012313:RNA / Q000096:biosynthesis; D051381:Rats; D013619:Tacrine / Q000378:metabolism* / Q000633:toxicity*; D014407:Tumor Cells, Cultured
chemical_list: D019384:Nucleic Acid Synthesis Inhibitors; D011500:Protein Synthesis Inhibitors; D013619:Tacrine; D012313:RNA; D019388:Cytochrome P-450 CYP1A2
vernacular_title: Absence de corrélation entre la cytotoxicité de la tacrine et sa métabolisation par le cytochrome P4501A2.